Electrochemical oxidative cyclization of N-allylamides for the synthesis of CF3-containing benzoxazines and oxazolines

The introduction of trifluoromethyl (–CF3) groups into compounds is a common synthetic strategy in organic chemistry. Commonly used methods for introducing trifluoromethyl groups are limited by harsh reaction conditions, low regioselectivity, or the need for excess reagents. In this study, a facile electrochemical oxidative and radical cascade cyclization of N-(2-vinylphenyl)amides for the synthesis of CF3-containing benzoxazines and oxazolines was obtained. This sustainable protocol features inexpensive and durable electrodes, a wide range of substrates, diverse functional group compatibility under transition-metal-free, external-oxidant-free, and additive-free conditions, and can be applied in an open environment.


Introduction
Heterocyclic compounds are one of the most important skeletons in organic synthesis, pharmaceutical chemistry, materials science and bioscience.Heterocycles containing N and O atoms play a crucial role in pharmaceuticals and functional molecules. 1Among these, benzoxazines and oxazolines are common privileged fragments frequently found in pharmaceutical molecules and biologically active compounds with remarkable biological activities, 2 such as anxiolytic, 3 anti-HIV, 4 progesterone receptor agonist, 5 anti-tuberculosis, 6 and anorectant activities 7 (Fig. 1).
Generally, the incorporation of uorinated moieties into molecules can signicantly change their physical, chemical, and biological properties.For example, the triuoromethyl (-CF 3 ) moiety is widely present in a variety of drugs (celecoxib, uoxetine, and trioxystrobin etc.), which can improve the efficacy, solubility, lipophilicity, metabolic stability, and binding selectivity. 8Efavirenz containing triuoromethyl benzoxazine shows potent anti-HIV activity. 4As a result, the potential values of these triuoromethylated benzoxazines and oxazolines have attracted signicant attention from chemists to develop efficient strategies for the construction of these intriguing molecule scaffolds. 9Xiao and co-workers reported a visible-light-induced photocatalytic triuoromethylation of Nallylamides for the synthesis of CF 3 -containing benzoxazines and oxazolines under Umemoto's reagent and Ru(bpy) 3 (PF 6 ) 2 (Scheme 1a).9m Similarly, Kumar's group developed a coppercatalyzed approach for construction of triuoromethylated benzoxazines by using Umemoto's reagent (Scheme 1b). 10 These methods are effective and versatile, but are limited to transitionmetal catalysts and Umemoto's reagent as CF 3 sources.In addition, Natarajan and colleagues disclosed a novel 9,10-phenanthrenedione visible-light photocatalysis protocol for the synthesis of triuoromethylated benzoxazines by using N-(2vinylphenyl)amides and triuoromethylsulnate under oxygen atmosphere (Scheme 1c).9a Nevertheless, it still requires additional photocatalysts and oxidants.Therefore, it is highly desirable to develop alternatively efficient, sustainable, green, and environmentally friendly synthetic methods avoiding transition metal catalysts and chemical oxidants.Organic electrochemistry provides an effective and sustainable strategy for the synthesis of valuable chemicals, employing inexpensive and renewable electrons as redox reagents. 11In our continuous efforts, our goal is to develop green, metal-free, and efficient methods to construct diversied heterocyclic scaffolds. 12In our previous work, we reported a direct azidation of benzylic C(sp 3 )-H bonds through an electrochemical process. 13erein, we'd like to report a new nding to construct tri-uorinated benzoxazines and oxazolines through an effective electrochemical strategy, which may use cheap carbon bre and nickel plates as electrodes in an undivided cell, without any external chemical oxidants, metal catalysts and additives (Scheme 1d).However, while we were preparing this manuscript, a similar work appeared, focusing on the construction of CF 2 -substituted benzoxazines, 14 in which the reaction system required triuoroacetic acid as a catalyst, adding complexity to the reaction system.In contrast, our reaction system is simpler and environmentally benign without the need for a transition metal catalyst or external oxidant, and can proceed smoothly with diverse functional group compatibility.

Results and discussion
Based on the above conception, we have attempted to achieve the CF 3 -containing benzoxazines by treatment of N-(2-(prop-1en-2-yl)phenyl)benzamide (1a) with CF 3 SO 2 Na.The reaction was carried out in an undivided cell equipped with a carbon bre (CF) anode and a nickel plate (Ni) cathode under a constant current of 5 mA (Table 1).The desired product 2a was obtained in 72% yield when n Bu 4 NPF 6 was used as the electrolyte in HFIP at 60 °C for 4 h (entry 1).We tried other electrolytes, such as Et 4 NBF 4 , n Bu 4 NOAc, n Bu 4 NBr, and n Bu 4 NI.Et 4 NBF 4 resulted in a signicant decrease (entry 2) in yield, only trace of the product was observed when using n Bu 4 NOAc and n Bu 4 NBr as electrolytes (entry 3), and the product was I-containing benzoxazine derivative when using n Bu 4 NI as the electrolyte (entry 4).Besides, the product 2a also was observed in the absence of electrolyte (entry 5).When we replaced solvent with DMSO (entry 6), CH 3 CN (entry 7), CH 3 OH (entry 8), and DCE (entry 9), all of them resulted in a slight decrease in the yield.This could be attributed to the ability of HFIP to stabilize radical cation intermediates, thereby aiding in substrate oxidation while preventing the product of overoxidation. 15We further evaluated other electrode materials, including Pt plate (entry 10), Fe plate (entry 11) as anode, and Fe plate (entry 12), Al plate (entry 13) as cathode, none of them was more effective.We transformed the current to 2 mA (entry 14) or 10 mA current (entry 15), the reaction efficiency was noticeably dropped in 2 mA current.The product 2a was decreased under 10 mA current, which Scheme 1 Strategies for the synthesis of trifluoromethylated benzoxazines.speculated that high current may cause peroxidation.The reaction temperature also was investigated, which led to lower yields (entries 16-18).When the equivalent of CF 3 SO 2 Na was reduced to 1, it resulted in a slight decrease in the yield (entry 19).Furthermore, electricity (entry 20) was essential for the process of the reaction.
With the optimal conditions in hand, the substrate scope of CF 3 -containing benzoxazines was explored (Scheme 2).Firstly, we introduced electron-donating groups or electronwithdrawing groups into N-(2-(prop-1-en-2-yl)phenyl) benzamide (1a) and they reacted smoothly to obtain corresponding products 2 in moderate to good yields, such as methyl (2b), methoxy (2c), and halides (2d, 2e, 2f, 2i, and 2j), especially the strong electron-withdrawing groups triuoromethyl (2g) and nitryl (2h) were all tolerant.Besides, we replaced the R 2 group by methyl (2k), tertiary butyl (2l), cyclopropyl (2m), cyclohexyl (2n), which reacted smoothly to afford the target product in good yields.Furyl (2o) or thienyl (2p) was transformed into the desired product in moderate yields, but pyridyl (2q) could not produce the target product.We speculated that the electron-withdrawing effect of pyridine made it difficult for 1q to generate the corresponding intermediate I or II.We also introduced morpholinyl (2r) and naphthyl (2s) into R 2 group, the target products were obtained.Further explorations about the R 1 group were hydrogen (2t) and phenyl (2u), the corresponding target compounds were also generated and showed great compatibility.In this synthetic system, CF 2 -substituted benzoxazines were also successfully synthesized using CF 2 -HSO 2 Na as the diuoromethylation reagent (31% yield for compound 2v), which indicates that the reaction system has good applicability.
We further explored the substrate scope of CF 3 -containing oxazolines, and the results were shown in Scheme 3. N-allylbenzamide 3a was reacted with CF 3 SO 2 Na to access the tri-uoromethylation product 2-phenyl-5-(2,2,2-triuoroethyl)-4,5dihydrooxazole (4a) in 59% yield.N-allylbenzamides with various substituents such as methyl (4b), methoxy (4c), halides (4d, 4e and 4f) were all tolerant.The benzene rings with electron-decient nitryl (4g) gave 82% yield.Meanwhile, when introducing furyl (4h) into the R 3 group, the corresponding target product also was obtained.But introducing cyclohexyl (4i) into R 3 group could not produce the target product, which indicated it had a very great inuence on this transformation.
To further evaluate the practicality and potential applications of this method, we performed the reaction on a gram-scale preparation with 1a, and the yield of product 2a was 60% under a constant current of 5 mA for 64 h (Scheme 4a).In addition, the product 2a can be further converted into 2-(2-(benzylamino) phenyl)-4,4,4-triuorobutan-2-ol (5) at a yield of 78% (Scheme 4b).
In order to investigate the possible mechanism of this transition, several control experiments were performed.No desired product was obtained when 2,2,6,6-Tetramethylpiperidoxyl (TEMPO) was added (Scheme 5).
A plausible mechanism for the formation of product has been proposed based on the related reports. 16As explained in Scheme 6, initially the HFIP undergoes cathodic reduction to Scheme 2 Substrate scope of CF 3 -containing benzoxazines.a Reaction conditions: undivided cell, 1 (0.25 mmol), CF 3 SO 2 Na/CF 2 HSO 2 -Na (0.5 mmol), n Bu 4 NPF 6 (0.5 mmol), HFIP (6 mL), under air atmosphere.To justify the proposed reaction pathway outlined in Scheme 6, we conducted cyclic voltammetric (CV) experiments.As shown in Fig. 2, the oxidation peak of CF 3 SO 2 Na was 0.83 V, and 1a had an oxidation peak of 1.32 V.These results indicated that CF 3 SO 2 Na was oxidized preferentially at the anode (see the ESI † for details).

Conclusions
In summary, we have developed a mild and efficient electrochemical oxidative and radical cascade cyclization of olenic amides to afford triuorinated benzoxazines and oxazolines using cheap and durable nickel plates as electrodes.This paper presents a simple, practical, green and environmentally benign protocol for the synthesis of uorinated benzoxazines and oxazolines.In the absence of any transition metal catalysts, external oxidizers and additives, this protocol proceeds smoothly with diverse functional group compatibility.
generate hydrogen gas at the cathode.At the anode, CF 3 SO 2 Na produces the CF 3 SO 2 radical under anodic oxidation and further forms the CF 3 radical.Subsequently, CF 3 radicals are added to the double bonds of the olens to generate the alkyl radical intermediate I.I undergoes a radical cyclization and anodic oxidation to furnish intermediate II.Aerwards, the intermediate II is nally converted into CF 3 -containing benzoxazine 2a by deprotonation (Scheme 6).

Scheme 5
Scheme 5 Control experiments of the reaction.